In the nervous system, neurons perform their function once they have formed a network through synapses between neurons by extending neurites (either axon or dendrite). In addition, such intercellular communication allows the cells to maintain their own existence through a mutual exchange of transmitters and nutritional factors. Therefore, even if the neurons themselves do not suffer fatal damage, if the neural network is damaged, neural functions decrease and, further, may lead to the death of the neurons themselves. Such neural network damage is thought to be what takes place first, not only in cases such as in external injuries where axons are disrupted, but also in many disorders causing neural damage, or in the surroundings of the damaged site. Therefore, a drug agent having a capability such as restoring neural network damage is thought to be both a drug agent capable of controlling the cellular death of neurons and an extremely active drug agent for the remedy of many disorders due to neural damage as well as lesion of nerves due to external injuries.
The following may be cited as disorders caused by neural damage: 1) Neuro-degenerative disorders such as Alzheimer's disease, Pick's disease, Lewy body disease, Parkinson's disease, Huntington's chorea, spinocerebellar degeneration and amyotrophic lateral sclerosis, 2) demyelinating disorders such as acute disseminated encephalomyelitis and multiple sclerosis, 3) metabolic disorders such as brain lipidosis and Wilson's Disease, 4) infectious disorders such as meningitis and Creutzfeld-Jacob disease, 5) peripheral neural disorders such as polyneuritis and Guillain-Barre Syndrome, 6) cerebrovascular disorder such as cerebral infarction and transient ischemia, 7) nervous disorders (neuropathies) associated with diabetes and renal diseases and 8) brain tumors.
Among the previously mentioned disorders which cause neural damage, Alzheimer's disease is the most representative, and constitutes a serious social issue together with the increase in the population of the elderly. In the past, the drug agents used for treating Alzheimer's disease could be roughly divided into those classified as activators of brain circulation and metabolism, and those classified as cholinergic nervous system activators. However, the activities of these drug agents are not sufficient.
In other words, activators of brain circulation and metabolism are drugs that are used to treat cerebrovascular damage and their after-effects, do not aid recovery directly from neural damage and therefore have a low efficacy against dementia which is the core disorder in Alzheimer's disease. In addition, activators of the cholinergic nervous system were developed based on the pathological findings that Alzheimer's disease patients had notable damage in the cholinergic nervous system. However, in Alzheimer's disease, cholinergic nervous systems are actually not the only ones that are damaged, therefore, the effects of such drugs are thought to be limited.
Given the situation, development of drugs based on novel drug effects for the treatment of Alzheimer's disease are strongly in demand. Among others, drug agents having an activity such as restoring neural network damage, as mentioned above, are anticipated to display extremely high efficacy for the treatment of Alzheimer's disease, if put into practical application.
In the past, for the development of drugs for the treatment of Alzheimer's disease, the models used for evaluating the drug's efficacy at the animal level were mainly models where the cholinergic nervous system was specifically damaged by methods such as administration of scoporamine or electric destruction, or models where damage was produced by cerebral ischemia or hypoxic stress due to carbon dioxide. Although many of these evaluation systems are reasonable as evaluation systems for the activators of the cholinergic nervous system or activators of brain circulation and metabolism, they are pathogenetically and pathologically distant from actual Alzheimer's disease, and are therefore not suited to the evaluation of novel drugs for the treatment of Alzheimer disease.
One important characteristic of Alzheimer's disease is the formation of senile plaques in the brain. β-amyloid proteins, which are the main constituents of these senile plaques, agglutinate in the brain to form amyloids and while being deposited in the brain tissue, exhibit their neurotoxicity, which is thought to be the main cause for Alzheimer's disease. Based on this, an animal model of Alzheimer's disease was made, wherein a mini-osmotic pump is implanted under the dorsal skin of a rat, for a continuous intracerebroventricular administration of β-amyloid proteins to lower the ability of learning and memory (Neuroscience Letters, vol. 170, pp. 63–66, 1994). In this model, deposition of the β-amyloid proteins could be recognized in the periphery of the cerebral ventricle. However, no clear neural cell death could be observed, therefore, there is a high possibility that the disorder of learning and memory observed in this model are due to damage in the neural network. Therefore, this model is an extremely rational system for screening and evaluating novel drugs for the treatment of Alzheimer's disease, and at the same time, is an adequate system for screening and evaluating novel drugs for the treatment of neural lesion due to a whole range of diseases causing neural damage, or due to injuries.
On the other hand, prostaglandin (PG) compounds are known to have multiple physiological activities such as strong platelet aggregation inhibition activity, vasodilatation and the associated hypotension activities, gastric acid secretion inhibition activity, smooth muscle contraction activity, cell protection activity, and diuretic activity. Based on such physiological activities, a number of attempts have been made to develop medicine from natural PG present in vivo, or from PG derivatives synthesized to serve as its agonists, and some of these attempts actually reached the market.
Prostacyclin, which is a PG, has the structure represented by the formula below (PGI2),
(in the formula, the numbers are identification numbers for the carbon atoms in prostacyclin) which is a substance containing a structure called α-chain comprising the carbon chain from 1 to 7, and a structure called ω-chain from carbon 13 to 20. In vivo it is known as a local hormone, mainly made in the vascular endothelium, and attempts were made to use its strong physiological activities, for example, platelet aggregation inhibition, smooth muscle contraction, hypotension, gastric acid secretion inhibition, peripheral vasodilatation and bronchodilatation, to provide it directly as a medicine (P. J. Lewis, J. O. Grady, Clinical Pharmacology of Prostaglandin).
However, because a prostacyclin molecule has a highly hydrolizable enol-ether bond, it is easily inactivated under neutral or acidic conditions, which makes it problematic in compounds to be used as medicines. Therefore, synthetic research was carried out on a compound having a prostacyclin analog structure, displaying the same activity as prostacyclin and being chemically stable (Synthesis, 1984, p. 449). In other words, this objective was achieved mainly by modifying the bicyclo[3.3.0]octane ring structure of from carbon 5 to 12 in prostacyclin. For example, the oxygen atoms bridging position 6 to 9 may be substituted with a methene group (—CH═) to synthesize the compound 9(O)-methano-Δ6(9α)-prostaglandin I1 (Isocarbacyclin) indicated by the formula below (Isocarbacyclin),
which is a compound having a prostacyclin analog structure fully satisfying the chemical stability (Japanese patent publication Sho. 59-210044). This compound displayed biological activities comparable to those of prostacyclin such as strong platelet aggregation inhibitory activity and vasodilatory-hypotensive activities (Japanese patent publication Sho. 59-210044 and Japanese patent publication Sho. 61-197518).
In the past, development of PG compounds to be used as medicine was mainly carried out in the field of obstetrics and gynecology, circulation or digestion. In the nerve field, there are no examples of these compounds commercialized as medicine, although there have been reports on the possibility of using PG compounds in nervous systems.
The following are known examples describing in particular the effect of compounds having a prostacyclin analog structure and which remedy neural damage: 1) in Japanese patent publication Sho. 61-129146, a compound having an isocarbacyclin analog structure was used for the prevention of or the treatment of the brain for disorders such as cerebral oxygen deficiency, 2) in Japanese patent publication Hei. 2-167227, a compound having an isocarbacyclin analog structure was used for the treatment of diabetic neuropathy, 3) in Japanese patent publication Hei. 8-245498, Japanese patent publication Hei. 10-101610, Japanese patent publication Hei. 11-5764 and patent No. EP-911314, a compound having an isocarbacyclin analog structure was used as a drug for the treatment of central nervous system disease, via the prostacyclin receptor of the central nervous system 4) in patent No. WO89/03387, 2,5,6,7-tetranor-4,8-inter-m-phenylene PGI2 derivative was used as a drug for the treatment of cerebral ischemia 5) in Japanese patent publication Hei. 2-262519, beraprost was used for the treatment of diabetic neuropathy, 6) in Japanese patent publication Sho. 63-141927, treatment and prevention of cerebral thrombosis and cerebral infarction.
In the previously mentioned examples, however, the efficacy is described for compounds with a carboxyl group at position 1 of the prostacyclin or an ester thereof. Only in the compounds having a prostacyclin analog structure described in the above mentioned 6), a compound having a prostacyclin analog structure wherein the carboxyl group at position 1 is substituted by an amide group is described. However, there is no concrete description related to its pharmacological activity. Therefore, the usability of a compound having a prostacyclin analog structure wherein the carboxyl group at position 1 is substituted with an amide group, as a drug for the remedy of neural damage, was not known.
On the other hand, most of the compounds of the past known to have a prostaglandin analog activity, are compounds having a prostacyclin analog structure with, at position 1, a carboxyl group which is thought to be important for expressing the activity, or a chemical structure that can be easily substituted with a carboxyl group in vivo. Therefore, there are only few publicly known substances having a prostacyclin analog structure with an amino group at the extremity of the α-chain. For example, the compound below, described in the (East) German patent No. DD266102,
(in the formula, the symbol  indicates the E or the Z configuration with respect to the attached double-bond and TBDMS represents a t-butyl-dimethylsilyl group). However, it is positioned as a synthetic intermediate, and a description of its activity is not available.
In addition, in the U.S. patent publication No. U.S. Pat. No. 4,226,984, the compounds having the structure indicated below
and their substituted versions on the (o-chain are described as having a stimulatory effect on smooth muscles. However, no concrete example is given.
In addition, in the Japanese patent publication Sho. 54-117450, a synthesis of the compound having the structure below
is described. However, no description on its activity is given.
In addition, in the Japanese patent publication Sho. 62-67046, the compounds of the scheme below
(in the scheme, THP represents tetrahydropyrane-2-yl group and TBDMS represents a t-butyl-dimethylsilyl group.) and their substituted versions on the ω-chain are described. However, no description of their activity is given.
In addition, in the Japanese patent publication Hei. 9-67285, the 4 compounds below
are described. However, no description of their activity is given.
In addition, in the detailed description of WO00/24727, only a description of the anti-helicobacter activity is given, of a derivative of the compound having an amino group at the extremity of the α-chain, comprising the compound indicated by the formula below,
and being a compound with a prostacyclin analog structure.
Therefore, most of the compounds having a prostacyclin analog structure with an amino group at the extremity of the α-chain were novel substances with no known usability.